**2. Historical overview of drug repurposing**

Drug repurposing, also known as indication shift, indication expansion, drug proofing, or drug repositioning, involves establishing a new medical use for an already known drug. These drugs can be experimental, shelved, discontinued, or already approved. Although drug repurposing is not a new strategy, it has gained wide recognition in recent times in the pharmaceutical sector [10].

The procedure to authorize a new medicine is costly and can take 10–15 years. This drawn-out discovery process makes drug repurposing (repositioning) a viable alternative strategy for reducing the amount of time needed to produce medicine. This original concept of drug repositioning has since been expanded to encompass active ingredients that failed the clinical stage of their development due to their toxicity or insufficient efficacy, as well as medications pulled off the market due to safety concerns. However, compounds that have not yet been the focus of clinical research

#### *COVID-19 Drug Development: Role of Drug Repurposing DOI: http://dx.doi.org/10.5772/intechopen.107939*

should not be included. This specifically disallows chemicals maintained in chemical libraries by academic and industrial research groups from being screened to find new biological qualities, apart from the properties for which they were initially developed and synthesized. Thus, any changes to the drug's structural makeup are not included in the idea of drug repositioning. Instead, repositioning uses either the biological properties for which the drug has already received approval (possibly in accordance with a different formulation, at a new dose, or via a new route of administration) or the side properties of a drug that are accountable for its negative effects in a new indication. The fact that various diseases share occasionally similar biological targets, as revealed by the elucidation of the human genome, and the idea of pleiotropic medications, serve as the two fundamental scientific foundations for therapeutic repositioning [11, 12]. Repurposing a medicine involves using it for a different indication after having it licensed by a regulatory body like the FDA, the European Medicines Agency (EMA), or the Medicines and Healthcare Products Regulatory Agency (MHRA), among others. Many pharmaceutical companies are presently using drug repurposing to regenerate some of their FDA-approved and previously unsuccessful pipeline molecules as novel medicines for a variety of illness conditions due to the enormous promise of a reduced development cycle [13, 14].

One of the keys to drug repurposing is the description of the factors related to the complicated interplay between diseases, medications, and targets using in silico methodologies (data mining, machine learning, ligand-based, and structure-based approaches). Today, diseases can be described in terms of their molecular profile (including the genes, biomarkers, signaling pathways, and environmental factors), and the degree of similarity between diseases that share a number of these molecular features can be assessed using computational methods, particularly data mining. Protein targets that are shared by a number of diseases imply that a given medication may be effective in treating both disorders [12, 15–17]. In terms of their core therapeutic effects and their (generally undesirable) side effects, the majority of medications are now phenotypically well described. The drug's pleiotropic interactions with a number of (primary and secondary) biological targets cause this variety of side effects. Therefore, if one of a medicine's secondary targets plays a part in an illness different than the one for which it was initially intended, the treatment may be effective against the new disease. Be aware that these pleiotropic interactions allow for the development of medications with many, intended effects that work in concert to increase clinical efficacy, such as the pan-kinase inhibitors used in cancer. Regardless of their therapeutic reason, medications can be analyzed for phenotypic similarities much like diseases are. A medicine may be successful for both indications if it has a high similarity score to another treatment designated for a separate condition [10, 16].

#### **2.1 Significance of drug repurposing**

Drug repurposing reduces the development cost for drugs because they have already gone through clinical trials, toxicity studies, and other tests [18]. **Tables 1** and **2** below show a list of some repurposed drugs in the past.A recent analysis based on a survey of 30 pharmaceutical and biotechnology companies found that the average cost to relaunch a repurposed drug is \$8.4 million, compared to an average cost of \$41.3 million for a new formulation of an existing drug in its original indication [20]. They have a higher success rate than the original drugs, owing to the availability of comprehensive information on their pharmacology, formulation, potential toxicity, safety, and adverse drug reaction issues, thereby reducing their attrition rate [21]. Since repurposing is based


#### **Table 1.**

*List of some drugs that have been repurposed.*

on prior research and development efforts, new drug candidates could be promptly prepared for clinical trials, hastening the FDA's review of them and, if approved, their introduction into healthcare, shortening the time it takes for the full processing cycle. Re-profiled medications also save the upfront costs and delays associated with bringing a drug to market, because it takes a great deal of time, money, and effort to produce a new medicine. In general, it frequently takes more than 15 years to convert a potential therapeutic candidate into an approved medication [22]. Therefore, it is essential to develop drug repurposing procedures in order to reduce the time and cost of drugs

*COVID-19 Drug Development: Role of Drug Repurposing DOI: http://dx.doi.org/10.5772/intechopen.107939*


#### **Table 2.**

*List of some repurposed drugs for the treatment of COVID-19.*

while also raising their success rates. In addition, repurposed compounds have a market penetration rate of 25% from Phase II and 65% from Phase III clinical trials, compared to 10% and 50%, respectively, for novel molecular entities [23].

For a new investigational molecule, safety and efficacy data are not yet available, resulting in higher attrition during the drug discovery process leading to the most failures regarding safety or efficacy. By contrast, all safety, preclinical, and efficacy data are readily available for a repurposed molecule, thus enabling the investigator to make an informed decision at each stage of drug development [23, 24]. Availability of prior knowledge regarding safety, efficacy, and the appropriate administration route significantly reduces the development costs and cuts down the development time resulting in less effort required for successfully bringing a repositioned drug to market [25]. For example, sildenafil, a phosphodiesterase type 5 (PDE5) inhibitor, represents one of the successful repurposing efforts. Sildenafil was originally developed for hypertension treatment but was later identified to have significant benefits in erectile dysfunction and was approved by the FDA for the same. It was later repurposed for the treatment of a rare disorder: pulmonary hypertension [26]. Also, daptomycin (an antibacterial agent) was repurposed for the treatment of Zika virus infection, chlorcyclizine (an antihistamine) was repurposed for the management of hepatitis C virus infection, and manidipine (an antihypertensive agent) was repurposed for Japanese encephalitis virus treatment [27].

### **3. Repurposed drugs for COVID-19 pandemic**

Due to the urgent need for COVID-19 treatment options, all repurposed drugs were given emergency approval. Approval for hydroxychloroquine and chloroquine were later revoked due to the high number of cardiac toxicity recorded (**Figure 2**) [10].

### **4. A simplified scheme of the life cycle of SARS-CoV-2**

Based on the likely mechanism by which registered pharmaceuticals combat the Coronavirus, the disease, or its symptoms, drug repurposing possibilities for COVID-19 can be categorized.

**Figure 2.** *Main organ injury of SARS-CoV-2 infection [24].*

